DESCRIPTION (verbatim from application) The Study of Osteoporotic Fractures (SOF) is a community-based prospective study in a cohort of 9,704 older women. SOF has comprehensive data about osteoporosis risk factors, along with an archive of serum, bully coat and urine specimens. Data from SOF have served for: (1) developing osteoporosis guidelines, (2) estimating the cost-effectiveness of screening for osteoporosis, and (3) planning trials of osteoporosis therapies. We propose to renew SOF to sustain this unique resource and to pursue several new hypotheses. Our preliminary findings suggest that BMD may lose predictive value for hip fractures after 4-5 years. We will study the long-term predictive value of BMD, and other risk factors, after 10-15 years; substantial declines would strongly effect guidelines concerning the frequency and cost-effectiveness of screening. We recently discovered that women with osteoporosis have a decreased risk of breast cancer, suggesting that these conditions share common etiologies. We will begin the search for these links by investigating whether endogenous sex steroids are associated with breast cancer, and whether other indices of osteoporosis, such as height loss, low ultrasound values, or incident fractures, indicate a lower risk of breast cancer. We have found that, contrary to previous beliefs, the rate of bone loss increases with age in Caucasian and African-American women. Elderly women also lose muscle mass as they age. We have also shown that mild chronic metabolic acidosis of dietary origin affects bone and causes negative nitrogen balance. We propose to test whether diet-induced metabolic acidosis, amplified by the normal age-related decline in renal function, is an important cause of loss of bone and muscle mass in elderly women, and is a risk factor for hip fracture. Declines in visual functions, such as contrast sensitivity, increase the risk of hip, wrist and humerus fractures and falls. Uncorrected refractive error and specific eye diseases, such as cataracts, glaucoma, and age-related macular degeneration, are common in elderly women. We will test the hypothesis that these common and potentially treatable eye diseases increase fall and fracture risk. Besides their scientific value, these findings may influence clinical guidelines and Medicare coverage for preventive eye care. Finally, there are contradictory findings about the relationship between estrogen receptor (ER) genotypes and bone mass and breast cancer, or even if ER variations have any biological effects. We propose using our archived DNA specimens and existing data about hip and vertebral fractures, breast cancer, bone mass, serum sex hormones and lipoproteins to determine whether these ER variations have biological importance.